B7-H3 is a protein having a single-pass transmembrane structure (Non-patent document 1). The N-terminal extracellular domain of B7-H3 contains two variants. Variant 1 contains a V-like or C-like Ig domain at two sites, respectively, and Variant 2 contains a V-like or C-like Ig domain at one site, respectively. The C-terminal intracellular domain of B7-H3 contains 45 amino acids.
As a receptor for B7-H3, TLT-2 having a single-pass transmembrane structure has been reported (Non-patent document 2). However, there is also a report insisting that TLT-2 is not a receptor for B7-H3 (Non-patent document 3). According to the former report, the activation of CD8-positive T cells is enhanced when the receptor is bound to B7-H3.
It has been clinically reported that B7-H3 is overexpressed in many cancer types, particularly in non-small-cell lung cancer, kidney cancer, urothelial carcinoma, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, and pancreatic cancer (Non-patent documents 4 to 11). Further, it has been reported that in prostate cancer, the intensity of expression of B7-H3 positively correlates with clinicopathological malignancy such as tumor volume, extraprostatic invasion, or Gleason score, and also correlates with cancer progression (Non-patent document 8). Similarly, in glioblastoma multiforme, the expression of B7-H3 negatively correlates with event-free survival (Non-patent document 9), and in pancreatic cancer, the expression of B7-H3 correlates with lymph node metastasis and pathological progression (Non-patent document 11). In ovarian cancer, the expression of B7-H3 correlates with lymph node metastasis and pathological progression.
Further, it has been reported that by introducing siRNA against B7-H3 gene into a B7-H3-positive cancer cell line, adhesiveness to fibronectin is reduced to reduce cell migration and matrigel invasion (Non-patent document 12). Further, it has been reported that in glioblastoma multiforme, the expression of B7-H3 allows escape from NK cell-mediated cell death (Non-patent document 13).
On the other hand, B7-H3 has been reported to be expressed not only in cancer cells, but also in tumors or surrounding vessels (Non-patent documents 5 and 14). It has been reported that when B7-H3 is expressed in ovarian cancer blood vessels, the survival rate is decreased.
B7 family molecules have been suggested to be related to the immune system. B7-H3 has been reported to be expressed in monocytes, dendritic cells, and activated T cells (Non-patent document 15). It has been reported that as cytotoxic T cells are activated, B7-H3 co-stimulates the proliferation of CD4-positive or CD8-positive T cells. However, there is also a report that B7-H3 does not play a co-stimulatory role (Non-patent document 1).
B7-H3 molecules have been reported to be related to autoimmune diseases. It has been reported that in rheumatism and other autoimmune diseases, B7-H3 plays an important role in the interaction between fibroblast-like synoviocytes and activated T-cells (Non-patent document 16) and that B7-H3 functions as a co-stimulatory factor when cytokines are released from activated macrophages and therefore is related to the occurrence of sepsis (Non-patent document 17). Further, it has been reported that by administering an anti-B7-H3 antibody to a mouse model of asthma during the induction phase, asthma is improved due to the suppression of Th2 cell-mediated cytokine production in regional lymph nodes through the administration of an anti-mouse B7-H3 antibody (Non-patent document 18).
With respect to B7-H3, it has been reported that an antibody against mouse B7-H3 enhances intratumoral infiltrating CD8-positive T cells and suppresses tumor growth (Non-patent document 14). Further, there is a patent which discloses that an antibody which recognizes B7-H3 variant 1 exhibits an in vivo antitumor effect on adenocarcinoma (Patent document 1).
In spite of these studies, an epitope for an anti-B7-H3 antibody which exhibits an in vivo antitumor effect has not been clarified so far, and there has been no report that a specific amino acid sequence of the extracellular domain of B7-H3 is useful as an epitope for a monoclonal antibody for treating cancer.
Even if antibodies are specific for the same antigen, the properties of the antibodies vary due to a difference of epitopes or sequences of the antibodies. Due to the difference in properties of the antibodies, when being clinically administrated to humans, the antibodies exhibit different reactions in terms of the effectiveness of the medicinal agent, the frequency of therapeutic response, the incidence of side effects or drug resistance, etc.
Also for the antibody against B7-H3, the creation of an antibody having unprecedented properties has been strongly demanded.